Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction

Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the forebrain and established a paradigm to examine the sensitivity of neurons to TDP-43 overexpression at different developmental stages. Continuous TDP-43 expression during early neuronal development produced a complex phenotype, including aggregation of phospho-TDP-43, increased ubiquitin immunoreactivity, mitochondrial abnormalities, neurodegeneration and early lethality. In contrast, later induction of hTDP-43 in the forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, phospho-TDP-43 neuronal cytoplasmic inclusions. These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 overexpression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies. Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies

Lentiviral vectors as tools to understand central nervous system biology in mammalian model organisms

Lentiviruses have been extensively used as gene delivery vectors since the mid-1990s. Usually derived from the human immunodeficiency virus genome, they mediate efficient gene transfer to non-dividing cells, including neurons and glia in the adult mammalian brain. In addition, integration of the recombinant lentiviral construct into the host genome provides permanent expression, including the progeny of dividing neural precursors. In this review, we describe targeted vectors with modified envelope glycoproteins and expression of transgenes under the regulation of cell-selective and inducible promoters. This technology has broad utility to address fundamental questions in neuroscience and we outline how this has been used in rodents and primates. Combining viral tract tracing with immunohistochemistry and confocal or electron microscopy, lentiviral vectors provide a tool to selectively label and trace specific neuronal populations at gross or ultrastructural levels. Additionally, new generation optogenetic technologies can be readily utilized to analyze neuronal circuit and gene functions in the mature mammalian brain. Examples of these applications, limitations of current systems and prospects for future developments to enhance neuroscience knowledge will be reviewed. Finally, we will discuss how these vectors may be translated from gene therapy trials into the clinical setting

A Mixed Multinomial Logit Model Analysis of Weekend Recreational Episode Type Choice

This paper presents a model for the type of recreational activity episodes that individuals pursue during the weekend. The choice set characterizing the type of recreational episode includes inhome, out-of-home, and pure recreational episodes (pure recreation refers to recreation trips pursued for the sole purpose of the recreational value obtained from the trip, such as walking, bicycling, and joy driving). The paper estimates a mixed multinomial logit formulation using the 2000 San Francisco Bay Area Travel Survey. The effects of household and individual sociodemographics, land-use and density variables, and episode participation attributes are examined. Inter-individual and intra-individual variation in unobserved determinants of episode type choice are also analyzed. Finally, the implications of the results for land-use and transportation planning are identified.Civil, Architectural, and Environmental Engineerin

A mixed multinomial logit model analysis of weekend recreational episode type choice

This paper presents a model for the type of recreational activity episodes that individuals pursue during the weekend. The choice set characterizing the type of recreational episode includes in-home, out-of-home, and pure recreational episodes (pure recreation refers to recreation trips pursued for the sole purpose of the recreational value obtained from the trip, such as walking, bicycling, and joy driving). The paper estimates a mixed multinomial logit formulation using the 2000 San Francisco Bay Area Travel Survey. The effects of household and individual sociodemographics, land-use and density variables, and episode participation attributes are examined. Inter-individual and intra-individual variation in unobserved determinants of episode type choice are also analyzed. Finally, the implications of the results for land-use and transportation planning are identified.